Exposure to drugs of abuse alter neuronal functioning, evident as both altered biology of the neurons and altered behaviors. Some of these changes long outlast the drug exposure. In parallel, there is also considerable evidence that exposure to drugs of abuse alters glial astrocyte morphology and function. Astrocytic glycogen serves as an energy reserve in the brain and its degradation is initiated during neuronal activation. Glycogen is metabolized on demand to lactate, which is then transported into neurons to serve as an energy substrate. Recent findings indicate that the contribution of astrocytes to energy metabolism in neurons is a key regulator of memory and neural plasticity. However, changes in astrocyte form and function have not been directly associated with the alteration in cognitive functions after exposure to drugs of abuse. We recently found that learning experiences, obtained during a single 1-hr training session, alter astrocytic glycogen storage and lactate production 30 days later in rats; these changes vary with task and brain area. This project extends these findings to test the effects of cocaine and morphine treatments on changes in glycogen levels and lactate production up to 30 days after drug exposure together with functional measures of astrocyte activity during later learning. Based on previously identified cognitive changes that differ after morphine and cocaine exposure, a multiple memory systems approach is applied here using neurochemical measures in striatum and hippocampus together with training on tasks that differentially engage these brain areas. This project will tes the hypotheses that cocaine and morphine exposure result in long-term changes in the contributions of astrocytes to brain energy metabolism with important consequences for enduring effects of drug experience on cognitive functions. The findings from these experiments may be foundational for future investigations into the nature of long-lasting changes in cognition and brain after drug experience. The contributions of astrocytes to altered bioenergetics after drug exposure, together with altered learning and memory abilities, may open new approaches to understanding and ameliorating the long-term consequences of drug exposures on brain and behavior.
In addition to long-term effects on neurons, drugs of abuse also have long-term effects on brain glial cells, which store glycogen from which lactate can be formed and delivered to neurons as a source of energy to supplement glucose supplies from blood. In rats, we found that glial-derived lactate is important for cognitive functions and that glial glycogen levels are changed for a long time after a single learning experience. This proposal examines the role of glycogen and lactate in the durable effects of cocaine and morphine on brain and behavior in rats, offering the potential of glia as targets for new treatments that may mitigate long-term drug effects on brain functions.
| Newman, Lori A; Scavuzzo, Claire J; Gold, Paul E et al. (2017) Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward. Neurobiol Learn Mem 137:142-153 |
